Slipping Past Cancer's Barriers

Getting a Step Ahead

The importance of biobarriers in cancer treatment led me to a startling thought: Perhaps the bunker itself is the cancer.

Diversity even within the same type of cells is a powerful mechanism of adaptation that confers major evolutionary advantages. The population of nominally identical cells that line the intestines modify themselves in response to a sustained change in diet, whereas those that form the skin respond to weather and environmental changes, and those in charge of repair following trauma reflect the nature of the injury. These adaptive modifications encode mass transport—what supplies enter and exit different body regions, in what amounts and rates—and extend beyond the cell level, to subcellular transport on one side and tissues and larger biological organizational scales on the other.

Cancer perhaps is a pathological presentation of these processes, the embodiment of the notion that too much of a good thing (such as healing from wounds or responding to environmental changes) can be detrimental to the organism as a whole. In this sense, perhaps cancer is not pathological on the scale of a large population; maybe it is the price that we as a species have to pay to be able to thrive and survive in milieus and conditions that require adaptability in how our body’s cells transport supplies and waste. Until, that is, we take control of our own evolution by developing treatments that allow us to keep collecting the benefits from the body’s adaptive transport mechanisms while effectively avoiding the suffering and death that result when they go awry.

Widely interdisciplinary teams are emerging to establish novel approaches to the treatment of metastatic cancer, and they seem to be keeping biological barriers in mind. We are now seeing the emergence of multistage cancer drugs, with each stage designed to traverse one or more biological barriers. In our laboratory, we have employed this approach to treat animal models of metastatic ovarian cancer and breast cancers with metastases to the lungs. In both of these new treatments we used multistage vectors, with the outer stage of delivery device made from a nanoporous silicon particle that harmlessly dissolves in the body after delivering its therapeutic payload.

For lung metastases, the first stages of these vectors were designed with physical properties (size, shape, surface charge) that maximized their concentration in the lungs. There, they released pDox, a polymer formation of the chemotherapeutic agent doxorubicin. Upon release inside of the tumor, pDox broke apart into nanoparticles, which were taken up by the target cells and carried by the cell’s vesicles to the vicinity of the nuclei. That location is where the drug is most effective, and the molecular pumps of the cell cannot expel the chemotherapy as efficiently. This combined treatment system resulted in the complete cure of about 50 percent of the animal models, and a great improvement in their survival times. The multistep action system is certainly complex, but no subcomponent of this process suffices to treat these metastases—and neither can anything else ever tried before.

The multistage vector system employed for treating ovarian cancer used nanoliposomes as the second stage and delivered a double dose of therapy: In addition to a conventional chemotherapy, paclitaxel, they also contained a small interfering RNA (siRNA). These short double-stranded RNA molecules are designed to interfere with the expression of specific genes. The multistage vector protected the siRNA from degradation in the body, and provided several weeks of sustained delivery of the therapeutic agent. This approach resulted in the complete remission of metastases in the peritoneum from the ovarian cancer. Again, a multistep solution worked for a problem that did not yield to single-step approaches.

Also promising are new molecularly targeted approaches, which have transformed cancer chemotherapy, and they are particularly promising when researchers can find a companion biomarker that measures the efficacy of the treatment for individual patients. The physics-based counterpart of the biomolecular approach to personalized precision lies in a combination of high- resolution medical imaging and engineering specific nanoscale vectors to transport cancer therapies. Innovation in imaging technology is making it possible to detect and quantify the modalities of mass transport in individual tumors. Using this information, researchers can use mathematical modeling to match an optimal nanovector with a target lesion.

With a combination of advances from different domains of science, I believe it will be possible to realize the century-old “magic bullet” vision of German physician and chemotherapy pioneer Paul Ehrlich, who won the Nobel Prize in Medicine in 1908. Now, as then, the goal is to obtain the greatest therapeutic benefit with the least adverse side effects. If the new, targeted nanomedicines succeed, it should then be possible to extend those therapies to treat the myriad diseases, often coexisting in the same person, that we collectively call “cancer.”